The long-term objective of the research described in the present proposal is to elucidate the neural mechanism(s) of dopamine (DA) receptor plasticity, especially as it relates to behavior. DA receptor plasticity is believed to be an important factor in the development of schizophrenia and tardive dyskinesia, and in the treatment of Parkinson's disease; it may also play a role in Tourette's syndrome and attention deficit/hyperactivity disorder. DA's actions are mediated by two main receptor subtypes, Dl and D2, the functions of which are normally interdependent and synergistic. However, the two receptor systems become functionally independent following selective destruction of DAergic neurons, a condition that is also known to result in behavioral supersensitivity to DA agonists and to increased numbers of D2 receptors. Although it is widely believed that the increase in D2 receptors is responsible for supersensitivity, research conducted by the principal investigator strongly refutes this notion. The present proposal will test the hypothesis that DA receptor sensitivity is directly and causally related to the state of Dl/D2 synergism. The specific aims of the proposal are: (l) to identify the stimuli that govern the maintenance and breakdown of DA Dl/D2 synergism; (2) to examine the relationship between DA receptor sensitivity and the state of Dl/D2 synergism; and (3) to identify the neural mechanism(s) of Dl/D2 synergism and supersensitivity. These objectives will be achieved by using a combination of behavioral and neurobiological methods. Systemic and intracerebral injection of DAergic, GABAergic and peptidergic drugs will be used to evaluate changes in the state of Dl/D2 synergism and behavioral sensitivity following various treatments. Immunocytochemical detection of FOS, enkephalin and substance P will be used to develop a histochemical model of Dl/D2 synergism.